We have shown that the neuropeptide galanin is a protective factor against behavioral and neurochemical correlates of opiate addiction in mice, including morphine-induced locomotor activation, conditioned place preference and withdrawal. Thus, galanin agonists would be potential pharmacological agents to decrease the abuse liability of opiates and polymorphisms in galanin-related genes might predispose individuals to drug abuse. We have found that galanin knockout mice show increased morphine-induced locomotion and conditioned place preference (CPP), and that these behavioral phenotypes are correlated with increased intracellular signaling through extracellular-regulated kinase (ERK) in the ventral tegmental area (VTA) and downstream target regions including the nucleus accumbens (NAc) and amygdala. We hypothesize that galanin normally decreases activity of the mesolimbic system, either directly through effects on dopamine (DA) neurons or indirectly through effects on acetylcholine (ACh) release, and that decreasing galanin activity increases sensitivity to morphine. This proposal will investigate the mechanisms responsible for the effects of galanin on morphine-induced locomotion and place preference by evaluating the ability of galanin to modulate DA and ACh release from striatal/NAc synaptosomes and measuring DA and ACh release in response to morphine in wild type mice treated with galanin and knockout mice lacking galanin (Gal-KO). We will determine whether galanin can modulate ACh activity in slices, and whether ACh is important for the hypersensitivity to morphine CPP in Gal-KO mice. We will identify the receptors important for its ability to decrease morphine CPP using knockout mice lacking different galanin receptor subtypes. Finally, we hypothesize that if galanin modulates mesolimbic excitability, it will also be protective against behavioral effects of other classes of addictive drugs, so we will determine whether cocaine-induced locomotion and CPP are altered in Gal-KO mice. These studies will be critical in characterizing an important protective factor that may protect against the development of drug addiction. We have shown that galanin is likely to be an important protective factor against the development of opiate addiction. Since we have shown that galanin can counteract both morphine reward and morphine withdrawal, galanin agonists would be interesting pharmacological agents to decrease the abuse liability of opiates prescribed for pain and to treat addicts who are attempting to become abstinent. In addition, genetic factors related to galanin signaling could be important determinants of whether individuals are susceptible to opiate addiction.